The overall theme of this Program Project Grant (P01) is to understand further the pathogenesis and genetics of asthma by studying environmental airway disease. We chose this theme for our PPG for the following reasons: 1) the symptoms and signs of asthma constitute a broad clinical phenotype; 2) asthma is a complex genetic disease caused by many biologically unique gene-gene and gene-environment interactions; 3) environmental models of airway disease serve to narrow the biological phenotype of asthma, providing an ideal opportunity to study the pathogenesis and genetics of this complex disease; and 4) this theme builds on existing scientific expertise and ensures a highly interactive program. Since acquired and innate mechanisms of immunity can function independently or interactively to cause or exacerbate asthma, we have chosen to use allergens and/or irritants (endotoxin and ozone) in the proposed projects to narrow the exposure-response phenotype and investigate the pathogenesis and genetics of environmental airway disease. The end result is a highly integrated and focused program that has the potential to make a number of novel, related observations. The primary hypothesis unifying this research program is that investigating environmental airway disease by modeling biologically unique gene-environment-asthma phenotypes will advance our understanding of the pathogenesis and genetics of asthma. The project-specific hypotheses proposal are: Project 1: Polymorphisms of genes expressed by airway cells in asthmatics following specific subsegmental airway challenges predispose individuals to the development of asthma. Project 2: Integrating the assessment of the environmental risk factors with an enhanced understanding of specific asthma susceptibility genes will lead to a coherent understanding of the relationship between genes, environment, and the development of asthma in an African American population. Project 3: Specific gene polymorphisms/mutations contribute to differential susceptibility to Oa-induced lung injury in asthmatic and normal subjects, and specific acquired host factors regulate injury from exposure to O3. Project 4: Alteration in airway SNO metabolism is important in the pathogenesis of asthma resulting in the dysregulation of airway cell apoptosis that contributes to the acute and chronic inflammatory changes seen in asthma. In aggregate, the coupled scientific findings in this program will substantially enhance our understanding of the pathogenesis and genetics of asthma.